Liver tumors activation

Anna CH, Maronpot RR, Pereira MA, et al. 1994. Ras proto-oncogene activation in dichloroacetic acid-, trichloroethylene-and tetrachloroethylene-induced liver tumors in B6C3F, mice. Carcinogenesis 15 2255-2261. 

Reynolds SH, Stowers SJ, Patterson RM, et al. 1987. Activated oncogenes in B6C3F, mouse liver tumors Implications for risk assessment. Science 237 1309-1316. 

It appears that considerable metabolism of nitrosamines takes place in the liver, from the finding that most of them are activated by rat liver microsomes to bacterial mutagens. However, relatively few nitrosamines induce liver tumors in rats. The most common target is the esophagus and a wide variety of nitrosamines induce tumors in this organ of rats, some only tumors of the esophagus, others tumors of other organs also. 

Dominguez, M. F., Macias, R. I., Izco-Basurko, I., de La Fuente, A., Pascual, M. J., Criado, J. M., Monte, M. J., Yajeya, J., Marin, J. J., Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors, J. Pharmacol. Exp. Ther. 2001, 297, 1106-1112. 

C. C. Lai, E. C. Miller, A. Liem, The Essential Role of Microsomal Deacetylase Activity in the Metabolic Activation, DNA-(Deoxyguanosin-8-yl)-2-aminofluorene Adduct Formation and Initiation of Liver Tumors by A-Hydroxy-2-acetylaminofluorene in the Livers of Infant Male B6C3Fj Mice , Carcinogenesis 1988, 9, 1295-1302. 

The access to hepatocytes with liver reconstituting activity is hindered by multiple obstacles, among them the very limited potential to expand hepatocytes in culture. Innate surveillance mechanisms linked to tumor suppressor... 

Hepatic Effects. No studies were located regarding hepatic effects in humans after exposure to 3,3 -dichlorobenzidine. Information from animal studies on the liver effects of exposure to 3,3 -dichloro-benzidine suggests that exposme to sufficiently high levels of the compoimd could cause liver injury as indicated by modest elevation in serum transaminase activity, fatty liver (Stula et al. 1978), decrease in hepatic vitamin E, and lipid peroxidation (Iba 1987a Iba and Lang 1988 Iba and Thomas 1988). Some of these effects may contribute to the liver tumors induced. However, it is not known whether these liver injuries will occur in humans exposed to 3,3 -dichlorobenzidine at levels at which it occurs at hazardous... 

All PCB mixmres adequately tested in mice and rats have shown carcinogenic activity. For example, of 20 rats fed Aroclor 1242 at 100 ppm in the diet for 24 months, 11 developed liver tumors, of which 3 were hepatomas. A significant incidence of hepatocellular neoplasms was found in female rats but not males in another smdy of Arochlor 1242 in the diet. Evidence from bioassays suggests that the less highly chlorinated PCBs (e.g., Aroclor 1242) have less carcinogenic potential than the more highly chlorinated mixtures (e.g., Aroclor 1254). ... 

Chrysene produced skin tumors after skin application to mice and has been shown to be active as a tumor initiator. Local tumors were observed after its subcutaneous injection in mice. Perinatal administration of chrysene to male mice by intraperitoneal injection increased the incidence of liver tumors, malignant lymphoma, and lung tumors. ... 

In 2-year gavage studies there was some evidence of carcinogenic activity in male rats based on increased incidences of cholangiocar-cinomas and bile duct dysplasia and fibrosis. There was also some evidence of carcinogenicity in female mice based on increased incidences of hepatocellular adenomas. Male mice showed clear evidence of carcinogenicity based on increased incidences of hepatocellular adenomas and carcinomas. The development of liver tumors may be related to the chronic inflammatory effects noted at this site. In another experiment with hamsters, exposure to furfural vapor 7 hours/day, 5 days/week for 1 year caused irritation of the nasal mucosa and growth retardation but no evidence of carcinogenic effects. ... 

Antitoxic effect. Sesame oil, adiministered to male Wistar rats, ameliorated hepatic and renal damage in a dose-dependent manner and increased survival in lipopolysaccha-ride-treated rats. It decreased lipid peroxide concentration in serum but not in liver and kidney. Serum nitrite production was unaffected by sesame oil ingestion, and the activity of xanthine oxidase was reduced in the lipopolysaccharide-challenged rats k Anti-tumor activity. Water extract of the dried seed, administered intragastrically to mice at a dose of 50 mg/animal daily for 5 days, was active on CA-Ehrlich-ascites, 18% increase in life-span. Intraperitoneal administration was active on Dalton s lyphoma and CA-Ehrlich-ascites, 19 and 39% increase in life-span, respectively ". Seed oil, administered to rats intraperito-neally with 1,2,5,6-dibenzanthracene or re-tene, was active on sarcoma ". 

SMANCS (Styrere-co-maleic acid/anhydride polymer bound to neocarzinostatin Neocarzinostatin (an antitumor protein) Amide bond between polymer carboxyl and protein amino None N/A SMANCS showed anticancer activity against many tumor cell lines, and had lower IC50 values than five other anticancer agents tested Liver tumors reduced more than 50% after 6 months in human subjects 15, 56, 57... 

Liver cancer can be induced in rats by localized irradiation (UNSCEAR, 1977) or by a number of different chemicals and dosage schedules (Farber, 1984). Initiation-promotion protocols are also effective inducers of liver tumors. The predominant lesions are preneoplastic nodules, but as in the skin, carcinomas arise late in the process. Altered hepatic cell fod can be identified within a few weeks after the start of carcinogen treatment by specific changes in enzyme activity, inability... 

The tumor initiating potential of PBBs is not well characterized. Numbers of GGT-altered foci were significantly increased in partially hepatectomized rats that were administered a single 1-10 mg/kg oral dose of 3,3, 4,4 -tetrabromobiphenyl followed by phenobarbital in the diet for 180 days (Dixon et al. 1988), indicating that PBBs may have initiating activity in hepatocarcinogenesis. Tlie potential for liver tumor initiation by PBBs appears to be weak compared to tlieir potent promoting activity (Buchmann et al. 1991 Dixon etal. 1988 Jensen et al. 1984). 

The question however is what happens in humans Fortunately, it seems that humans have more glucuronosyl transferase activity than mice and much more than (100 x) rats (in which it is negligible). Furthermore, humans have much lower levels (5x) of sulfotransferase activity with this substrate, and so humans are the opposite extreme to rats. In studies in women treated with tamoxifen, no DNA adducts were detected in tissue samples, and liver tumors have not been detected. 

Carbon tetrachloride causes centrilobular liver necrosis and steatosis after acute exposure, and liver cirrhosis, liver tumors, and kidney damage after chronic administration. The mechanism underlying the acute toxicity to the liver involves metabolic activation by cytochrome P-450 to yield a free radical (trichloromethyl free radical). This reacts with unsaturated fatty acids in the membranes of organelles and leads to toxic products of lipid peroxidation including malondialdehyde and hydroxynonenal. This results in hepatocyte necrosis and inhibition of various metabolic processes including protein synthesis. The latter leads to steatosis as a result of inhibition of the synthesis of lipoproteins required for triglyceride export. 

Amra, C.H., Maronpot, R.R., Pereira, M.A., Foley, J.F., Malarkey, D.E. Anderson, M.W. (1994) ras Proto-oncogene activation in dichloroacclic acid-, trichloroethylene- and tetrachloro-ethylene-induced liver tumors inB6C3Fl mice. Carcinogenesis, 15, 2255-2261... 

The manner in which the reduction of ribonucleotides to deoxyribonucleotides is regulated has been studied with reductases from relatively few species. The enzymes from E. coli and from Novikoff s rat liver tumor have a complex pattern of inhibition and activation (fig. 23.25). ATP activates the reduction of both CDP and UDP. As dTTP is formed by metabolism of both dCDP and dUDP, it activates GDP reduction, and as dGTP accumulates, it activates ADP reduction. Finally, accumulation of dATP causes inhibition of the reduction of all substrates. This regulation is reinforced by dGTP inhibition of the reduction of GDP, UDP, and CDP and by dTTP inhibition of the reduction of the pyrimidine substrates. Because evidence suggests that ribonucleotide reductase may be the rate-limiting step in deoxyribonucleotide synthesis in at least some animal cells, these allosteric effects may be important in controlling deoxyribonucleotide synthesis. 

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